1. Field of the Invention
The present invention relates to a new means for the treatment of focal ischemic cerebral infarction ischemic stroke.
2. Description of the Related Art
Focal ischemic cerebral infarction occurs when the arterial blood flow to a specific region of the brain is reduced below a critical level resulting in neuronal cell death. It is thought that neuronal degeneration in central nervous system (CNS) diseases such as stroke, epilepsy and Alzheimer's disease is stimulated by an excess of the excitatory amino acid glutamate (2). Injection of glutamate agonists in the CNS indeed induces hippocampal neuronal cell death similar to that observed in neurodegenerative diseases (3).
Excitotoxin-induced neuronal degeneration is mediated by tissue-type plasminogen activator (t-PA) (4). Consistent with this observation, mice deficient in t-PA are resistant to, and infusion of plasminogen activator inhibitor-1 (PAI-1) protects against excitotoxin-mediated hippocampal neuronal degeneration (4-6).
Furthermore, deficiency of plasminogen (Plg), the zymogen substrate of t-PA, and infusion of α2-antiplasmin (α2-AP), protect mice against excitotoxin-induced hippocampal neuronal death (5). It has been proposed that plasmin-mediated degradation of laminin sensitizes hippocampal neurons to cell death by disrupting neuron-extracellular matrix interaction (7).
Wang et al. (8) recently demonstrated that neuronal damage after focal cerebral ischemia induced by transient occlusion of the middle cerebral artery was also reduced in mice with t-PA deficiency and exacerbated by t-PA infusion. This suggests that the plasminogen system may be involved both in establishing a cerebral ischemic infarct and in its extension during thrombolytic therapy. It was recently demonstrated that the neurotoxic effect of t-PA on persistent focal cerebral ischemia also occurred with other thrombolytic agents, including streptokinase and staphylokinase (9). Thus, in those patients with persistent cerebral arterial occlusion, thrombolytic therapy for ischemic stroke may cause infarct extension, which would not only partially offset the established overall beneficial effect of arterial recanalization (10, 11), but indeed be harmful to a subgroup of patients. Because it is not possible to distinguish between patients who will and those who will not achieve cerebral arterial recanalization with thrombolytic therapy, the development of specific conjunctive strategies to counteract the neurotoxic effects of thrombolytic agents on persisting focal cerebral ischemia appear to be warranted.